Antimicrobial agents

ABSTRACT

The invention provides methods of treating a bacterial infection in a mammal comprising administering to the mammal a substituted bicyclic heteroaromatic ring compound of formula I: wherein two of X 1  to X 8  are N and the remaining of X 1  to X 8  are CH; or a pharmaceutically acceptable salt thereof, as well as novel compounds of formula I and salts thereof and pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof.

PRIORITY OF INVENTION

This application claims priority from U.S. Provisional Application No.61/586,583 filed 13 Jan. 2012, which application is incorporated byreference.

BACKGROUND OF THE INVENTION

The emergence of Multidrug Resistant (MDR) bacterial pathogens (e.g.methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacterbaumannii-calcoaceticus complex (ABC), etc.) has increased concerns asto the adequacy of current antimicrobials and pathogen treatmentmethods. The lethality of such pathogens, particularly MRSA, has oftenled to treatment methods that are experimental or would otherwisenormally be avoided in standard clinical practice. For example, theantibiotic colistin was traditionally considered too nephrotoxic andneurotoxic for clinical use, but is nevertheless used to treat many MDRbacterial infections due to a paucity of available active drugs. Thegrowing threat from MDR pathogens highlights a critical need foradditional antimicrobials. In this connection, there is a pressing needfor new antibiotics that exhibit novel mechanisms of action or that areable to circumvent known resistance pathways.

Elements of the bacterial cell division machinery present targets forantimicrobial compounds because (i) they are essential for bacterialviability, (ii) they are widely conserved among bacterial pathogens, and(iii) they often have markedly different structures than theireukaryotic homologs. One such protein that has been identified as apotential target is the FtsZ protein. During the division process, FtsZ,along with approximately 15 other proteins, assemble at mid-cell into alarge cell division complex (termed the divisome), ultimatelyfacilitating cell cytokinesis. More importantly, FtsZ is widelyconserved among many bacterial strains.

SUMMARY OF THE INVENTION

In one embodiment the invention provides compounds that displayantimicrobial activity. Accordingly, the invention provides a method fortreating a bacterial infection in a mammal comprising administering tothe mammal an effective amount of a bicyclic heteroaromatic ringcompound of formula I:

wherein:

two of X₁ to X₈ are N and the remaining of X₁ to X₈ are CH; and

the bicyclic heteroaryl ring is a) substituted on a first ring carbonwith a group R¹ and substituted on a second ring carbon with a group R²;or is b) substituted on a ring carbon with a group R¹ and substituted ona ring nitrogen with R³ to form the corresponding ammonium salt that hasa suitable counter ion X⁻; or is c) substituted on a ring carbon with agroup R⁴;

R¹ is phenyl that is optionally substituted with one or more groupsindependently selected from halo, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₆)alkoxycarbonyl, —C(═O)NR^(e)R^(f), and phenyl that is optionallysubstituted with one or more halo, (C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl;

R² is —NR^(c)R^(d), —N⁺(R^(a))₃Z⁻, —C(═NR^(a))—NR^(c)R^(d),—NR^(a)—C(═NR^(a))—NR^(c)R^(d), —NR^(a)—C(═NR^(a))—R^(a),—NR^(a)—NR^(a)—C(═NR^(a))—NR^(c)R^(d),—C(H)═N—NR^(a)—C(═NR^(a))—NR^(c)R^(d),—C(═O)—NR^(a)—C(═NR^(a))—NR^(c)R^(d), —C(═O)—NR^(a)—C(═NR^(a))—R^(a), orR^(b); or R² is (C₁-C₆)alkyl that is substituted with —NR^(c)R^(d),—N⁺(R^(a))₃Z⁻, —C(═NR^(a))—NR^(c)R^(d), —NR^(a)C(═NR^(a))—NR^(c)R^(d),—NR^(a)—C(═NR^(a))—R^(a), —NR^(a)—NR^(a)—C(═NR^(a))—NR^(c)R^(d),—C(H)═N—NR^(a)—C(═NR^(a))—NR^(c)R^(d),—C(═O)—NR^(a)—C(═NR^(a))—NR^(c)R^(d), —C(═O)—NR^(a)—C(═NR^(a))—R^(a), orR^(b);

R³ is (C₁-C₆)alkyl;

each R⁴ is independently phenyl that is substituted with one or more R²or —C(═O)NR^(m)R^(n) and that is also optionally substituted with one ormore halo, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxycarbonyl, orphenyl that is optionally substituted with one or more halo,(C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl;

each R^(a) is independently H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl andheteroaryl(C₁-C₆) alkyl;

each R^(b) is independently selected from imidazoyl, piperazinyl,triazole, and piperazinyl that is optionally substituted with(C₁-C₆)alkyl;

each R^(c) and R^(d) is independently selected from H, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl,aryl(C₁-C₆)alkyl and heteroaryl(C₁-C₆)alkyl wherein any (C₁-C₆)alkyl ofR^(c) and R^(d) is optionally substituted with one or more hydroxy oramino; or R^(c) and R^(d) together with the nitrogen to which they areattached form a aziridino, azetidino, morpholino, piperazino,pyrrolidino or piperidino;

each R^(e) and R^(f) is independently selected from H, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl,aryl(C₁-C₆)alkyl and heteroaryl(C₁-C₆)alkyl wherein any (C₁-C₆)alkyl isoptionally substituted with one or more hydroxy or amino; or R^(e) andR^(f) together with the nitrogen to which they are attached form aaziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;

each R^(m) and R^(n) is independently selected from H, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl,aryl(C₁-C₆)alkyl and heteroaryl(C₁-C₆)alkyl wherein any (C₁-C₆)alkyl ofR^(m) and R^(n) is optionally substituted with one or more amino; orR^(m) and R^(n) together with the nitrogen to which they are attachedform a aziridino, azetidino, morpholino, piperazino, pyrrolidino orpiperidino; and

each Z⁻ is independently a suitable counter ion;

or a pharmaceutically acceptable salt thereof.

The invention also provides a novel compound of formula I or a saltthereof.

The invention also provides a composition comprising a compound offormula I, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable vehicle.

The invention also provides a compound of formula I or apharmaceutically acceptable salt thereof for the prophylactic ortherapeutic treatment of a bacterial infection.

The invention also provides a compound of formula I or apharmaceutically acceptable salt thereof for use in medical treatment.

The invention also provides the use of a compound of formula I or apharmaceutically acceptable salt thereof for the preparation of amedicament for treating a bacterial infection in a mammal.

The invention also provides processes and intermediates disclosed hereinthat are useful for preparing compounds of formula I or salts thereof.

DETAILED DESCRIPTION

The following definitions are used, unless otherwise described: halo isfluoro, chloro, bromo, or iodo. Alkyl and alkoxy, etc. denote bothstraight and branched groups but reference to an individual radical suchas propyl embraces only the straight chain radical (a branched chainisomer such as isopropyl being specifically referred to). In oneembodiment alkyl is a (C₁-C₆)alkyl and alkoxy is a (C₁-C₆)alkoxy. Aryldenotes a phenyl radical or an ortho-fused bicyclic carbocyclic radicalhaving about nine to ten ring atoms in which at least one ring isaromatic. Heteroaryl encompasses a radical of a monocyclic aromatic ringcontaining five or six ring atoms consisting of carbon and one to fourheteroatoms each selected from the group consisting of non-peroxideoxygen, sulfur, and N(Q) wherein Q is absent or is H, O, (C₁-C₄)alkyl,phenyl or benzyl; as well as a radical of an ortho-fused bicyclicheterocycle of about eight to ten ring atoms comprising one to fourheteroatoms each selected from the group consisting of non-peroxideoxygen, sulfur, and N(Q).

As used herein “cycloalkyl” refers to a saturated or partiallyunsaturated cyclic hydrocarbon ring system. In one embodiment“cycloalkyl” includes (C₃-C₆)cycloalkyl which can be cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl.

When the bicyclic heteroaryl ring in formula I is substituted on a ringcarbon with R¹, R², or R⁴ as defined herein it should be understood thatthe hydrogen atom of the corresponding X₁ to X₈CH group is removed andreplaced with the R¹, R², or R⁴ group.

It will be appreciated by those skilled in the art that compounds of theinvention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, stereoisomeric, orpolymorphic form, or mixtures thereof, of a compound of the invention,which possess the useful properties described herein, it being wellknown in the art how to prepare optically active forms (for example, byresolution of the racemic form by recrystallization techniques, bysynthesis from optically-active starting materials, by chiral synthesis,or by chromatographic separation using a chiral stationary phase).

It will also be appreciated by those skilled in the art that certaincompounds of the invention can exist in more than one tautomeric form.For example, a substituent of formula —NH—C(═NH)—NH₂ in a compound offormula (I) could exist in tautomeric form as —N═C(NH₂)—NH₂, or asubstituent of formula —NH—C(═NH)—CH₃ in a compound of formula (I) couldexist in tautomeric form as —N═C(NH₂)—CH₃. The present inventionencompasses all tautomeric forms of a compound of formula I as well asmixtures thereof that can exist in equilibrium with non-charged entitiesdepending upon pH, which possess the useful properties described herein.

Specific values listed below for radicals, substituents, and ranges, arefor illustration only; they do not exclude other defined values or othervalues within defined ranges for the radicals and substituents.

Specifically, (C₁-C₆)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;(C₃-C₆)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl; (C₁-C₆)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy,butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy;(C₁-C₆)alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, orhexyloxycarbonyl; aryl can be phenyl, indenyl, or naphthoyl; andheteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl,isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl,tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or itsN-oxide), indolyl, benzimidazole, isoquinolyl (or its N-oxide) orquinolyl (or its N-oxide).

As used herein the term “aryl(C₁-C₆)alkyl” refers to a (C₁-C₆)alkylradical in which one or more of the hydrogen atoms of the (C₁-C₆)alkylradical is replaced with an aryl radical. As used herein the term“heteroaryl(C₁-C₆) alkyl” refers to a (C₁-C₆)alkyl radical in which oneor more of the hydrogen atoms of the (C₁-C₆)alkyl radical is replacedwith a heteroaryl radical. As used herein the term“(C₃-C₆)cycloalkylC₁-C₆)alkyl” refers to a (C₁-C₆)alkyl radical in whichone or more of the hydrogen atoms of the (C₁-C₆)alkyl radical isreplaced with a (C₃-C₆)cycloalkylradical.

In one embodiment of the invention the compound of formula I is abicyclic ring selected from:

wherein the bicyclic ring is a) substituted on a first ring carbon witha group R¹ and substituted on a second ring carbon with a group R²; oris b) substituted on a ring carbon with a group R¹ and substituted on aring nitrogen with R³ to form the corresponding ammonium salt that has asuitable counter ion X⁻; or is c) substituted on a ring carbon with agroup R⁴.

In one embodiment of the invention the compound of formula I is abicyclic ring of formula:

that is a) substituted on a first ring carbon with a group R¹ andsubstituted on a second ring carbon with a group R²; or is b)substituted on a ring carbon with a group R¹ and substituted on a ringnitrogen with R³ to form the corresponding ammonium salt that has asuitable counter ion X⁻; or is c) substituted on a ring carbon with agroup R⁴.

In one embodiment of the invention the compound of formula I is abicyclic ring of formula:

that is a) substituted on a first ring carbon with a group R¹ andsubstituted on a second ring carbon with a group R²; or is b)substituted on a ring carbon with a group R¹ and substituted on a ringnitrogen with R³ to form the corresponding ammonium salt that has asuitable counter ion X⁻; or is c) substituted on a ring carbon with agroup R⁴.

In one embodiment of the invention the compound of formula I is abicyclic ring of formula:

that is a) substituted on a first ring carbon with a group R¹ andsubstituted on a second ring carbon with a group R²; or is b)substituted on a ring carbon with a group R¹ and substituted on a ringnitrogen with R³ to form the corresponding ammonium salt that has asuitable counter ion X⁻; or is c) substituted on a ring carbon with agroup R⁴.

In one embodiment of the invention the compound of formula I is abicyclic ring of formula:

that is a) substituted on a first ring carbon with a group R¹ andsubstituted on a second ring carbon with a group R²; or is b)substituted on a ring carbon with a group R¹ and substituted on a ringnitrogen with R³ to form the corresponding ammonium salt that has asuitable counter ion X⁻; or is c) substituted on a ring carbon with agroup R⁴.

In one embodiment of the invention the compound of formula I is selectedfrom:

In one embodiment of the invention the compound of formula I is has aformula selected from:

In one embodiment of the invention the compound of formula I has thefollowing formula:

In one embodiment of the invention the compound of formula I is has thefollowing formula:

In one embodiment of the invention R¹ is phenyl, 3-biphenyl,3-tert-butylphenyl, 4-tert-butylphenyl, 3-fluorophenyl,3-methoxycarbonyl-5-(4-tert-butylphenyl)phenyl,3-aminocarbonyl-5-(4-tert-butylphenyl)phenyl,3-(N-(2-hydroxyethyl)aminocarbonyl)-5-(4-tert-butylphenyl)phenyl, or3-methylphenyl.

In one embodiment of the invention R² is guanadinomethyl, aminomethyl,N-(2-aminoethyl)amino, or —CH₂—NH—C(═NH)CH₃.

In one embodiment of the invention R³ is methyl and X⁻ is I⁻.

In one embodiment of the invention the compound of formula I is has thefollowing formula:

In one embodiment of the invention R⁴ is3-(N-(2-aminoethyl)aminocarbonyl)-5-(4-tert-butylphenyl)phenyl.

In one embodiment the invention provides a compound selected fromcompounds 1-22 and salts thereof.

In one embodiment the compound of the invention is not compound 10 orcompound 20 or a salt thereof.

In one embodiment the invention provides a compound selected fromcompounds of formula I and salts thereof having a minimal inhibitoryconcentration against MSSA of less than about 16 μm (see Test C below).

In one embodiment the invention provides a compound selected fromcompounds of formula I and salts thereof having a minimal inhibitoryconcentration against MSSA of less than about 8 μm.

In one embodiment the invention provides a compound selected fromcompounds of formula I and salts thereof having a minimal inhibitoryconcentration against MSSA of less than about 4 μm.

In one embodiment the invention provides a compound selected fromcompounds of formula I and salts thereof having a minimal inhibitoryconcentration against MSSA of less than about 2 μm.

Generally, compounds of formula I as well as synthetic intermediatesthat can be used for preparing compounds of formula I, can be preparedas illustrated in the following Schemes. It is understood that variablegroups shown in the Schemes below (e.g. R₁, R₂, R₃, Ar₁, and Ar₂) canrepresent the final corresponding groups present in a compound offormula I or that these groups can represent groups that can beconverted to the final corresponding groups present in a compound offormula I at a convenient point in a synthetic sequence. For example, inthe Schemes below, the variable groups can contain one or moreprotecting groups that can be removed at a convenient point in asynthetic sequence to provide the final corresponding groups in thecompound of formula I.

Processes for preparing compounds of formula I are provided as furtherembodiments of the invention and are illustrated by the followingprocedures in which the meanings of the generic radicals are as givenabove unless otherwise qualified.

By binding to FtsZ, the compounds of the present invention inhibit theability of the protein to hydrolyze GTP. This inhibition of FtsZ GTPaseactivity, in turn, inhibits the ability of the protein to polymerizeinto Z-rings, as Z-ring formation requires GTP hydrolysis as an energysource for driving the reaction. Since the Z-ring serves as the scaffoldfor recruitment of all other proteins that comprise the divisomecomplex, inhibition of Z-ring formation by the compounds of the presentinvention also results in a corresponding inhibition of divisome proteinrecruitment.

The compounds of the invention are useful to treat bacterial infectionsincluding infections by Gram-negative bacterial strains, Gram-positivebacterial strains and multiple drug-resistant bacterial strains

Gram-negative bacterial strains include Escherchia coli, Caulobactercrescentus, Pseudomonas aeruginosa, Agrobacterium tumefaciens,Branhamella catarrhalis, Citrobacter diversus, Enterobacter aerogenes,Enterobacter cloacae, Enterobacter sakazakii, Enterobacter asburiae,Pantoea agglomerans, Klebsiella pneumoniae, Klebsiella oxytoca,Klebsiella rhinoscleromatis, Proteus mirabilis, Salmonella typhimurium,Salmonella enteriditis, Serratia marcescens, Shigella sonnei, Neisseriagonorrhoeae, Acinetobacter baumannii, Acinetobacter calcoaceticus,Acinetobacter lwoffi, Fusobacterium nucleatum, Veillonella parvula,Bacteroides forsythus, Actinobacillus actinomycetemcomitans,Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis,Helicobacter pylori, Francisella tularensis, Yersinia pestis, Borreliaburgdorferi, Neisseria meningitidis and Haemophilus influenza.

Gram-positive bacterial strains include Staphylococcus aureus,Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcuspyogenes, Streptococcus faecalis, Enterococcus faecalis, Enterococcusfaecium, Bacillus subtilis, Bacillus anthracis, Bacillus cereus,Micrococcus luteus, Mycobacterium tuberculosis, Clostridium difficile,Propionibacterium acnes, Streptococcus mutans, Actinomyces viscosus,Actinomyces naeslundii, Streptococcus sanguis, Streptococcus pneumoniae,Streptococcus viridans and Streptococcus salivarius.

Multiple drug-resistant bacterial strains include methicillin-resistantStaphylococcus aureus, vancomycin-resistant Enterococci, multipledrug-resistant Mycobacterium tuberculosis, and multidrug-resistantClostridium difficile.

In one embodiment compounds of the present invention may be administeredas a composition used to treat and/or prevent a bacterial infectionwherein the bacterial cell uses polymerized FtsZ protein, or a homologthereof, to facilitate cytokinesis. To this end, compounds of thepresent invention may be administered to treat Staph Infections,Tuberculosis, Urinary Tract Infections, Meningitis, Enteric Infections,Wound Infections, Acne, Encephalitis, Skin Ulcers, Bed Sores, Gastricand Duodenal Ulcers, Eczema, Periodontal disease, Gingivitis, Halitosis,Anthrax, Tularemia, Endocarditis, Prostatitis, Osteomyelitis, LymeDisease, Pneumonia, or the like.

The compositions can, if desired, also contain other active therapeuticagents, such as a narcotic, a non-steroid anti-inflammatory drug(NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, aneuromuscular blocker, an anti-cancer, other antimicrobial (for example,an aminoglycoside, an antifungal, an antiparasitic, an antiviral, acarbapenem, a cephalosporin, a fluororquinolone, a macrolide, apenicillin, a sulfonamide, a tetracycline, another antimicrobial), ananti-psoriatic, a corticosteriod, an anabolic steroid, adiabetes-related agent, a mineral, a nutritional, a thyroid agent, avitamin, a calcium-related hormone, an antidiarrheal, an anti-tussive,an anti-emetic, an anti-ulcer, a laxative, an anticoagulant, anerythropieitin (for example, epoetin alpha), a filgrastim (for example,G-CSF, Neupogen), a sargramostim (GM-CSF, Leukine), an immunization, animmunoglobulin, an immunosuppressive (for example, basiliximab,cyclosporine, daclizumab), a growth hormone, a hormone replacement drug,an estrogen receptor modulator, a mydriatic, a cycloplegic, analkylating agent, an anti-metabolite, a mitotic inhibitor, aradiopharmaceutical, an anti-depressant, an anti-manic agent, ananti-psychotic, an anxiolytic, a hypnotic, a sympathomimetic, astimulant, donepezil, tacrine, an asthma medication, a beta agonist, aninhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn,an epinephrine or analog thereof, dornase alpha (Pulmozyme), a cytokine,or any combination thereof.

The term “prodrug” as used herein refers to any compound that whenadministered to a biological system (e.g. a mammal such as a human)generates the drug substance, i.e. active ingredient, as a result ofspontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s),photolysis, and/or metabolic chemical reaction(s) or by some otherprocess. A prodrug is thus a modified (e.g. covalently modified) analogor latent form of a therapeutically-active compound. A prodrug may alsobe an active metabolite or therapeutically-active compound itself.

By way of example a prodrug may generate the active inhibitory compoundduring metabolism, systemically, inside a cell, by hydrolysis, enzymaticcleavage, or by some other process (Bundgaard, Hans, “Design andApplication of Prodrugs” in A Textbook of Drug resign and Development(1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood AcademicPublishers, pp. 113-191; Tranoyl-Opalinski, I., Fernandes, A., Thomas,M., Gesson, J.-P., and Papot, S., Anti-Cancer Agents in Med. Chem., 8(2008) 618-637). Enzymes which are capable of an enzymatic activationmechanism with the prodrug compounds of the invention include, but arenot limited to nitroreductase, proteases (e.g. serine proteases such asprostate specific antigen (PSA), amidases, esterases, microbial enzymes,phospholipases, cholinesterases, and phosphases).

In cases where compounds are sufficiently basic or acidic, a salt of acompound of formula I can be useful as an intermediate for isolating orpurifying a compound of formula I. Additionally, administration of acompound of formula I as a pharmaceutically acceptable acid or base saltmay be appropriate. Examples of pharmaceutically acceptable salts areorganic acid addition salts formed with acids which form a physiologicalacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tartrate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts mayalso be formed, including hydrochloride, sulfate, nitrate, bicarbonate,and carbonate salts. Salts may be obtained using standard procedureswell known in the art, for example by reacting a sufficiently basiccompound such as an amine with a suitable acid affording thecorresponding anion. Alkali metal (for example, sodium, potassium orlithium) or alkaline earth metal (for example calcium) salts ofcarboxylic acids can also be made.

Pharmaceutically suitable counterions include pharmaceutically suitablecations and pharmaceutically suitable anions that are well known in theart. Examples of pharmaceutically suitable anions include, but are notlimited to those described above (e.g. physiologically acceptableanions) including Cl⁻, Br⁻, I⁻, CH₃SO₃ ⁻, CF₃SO₃ ⁻, p-CH₃C₆H₄SO₃ ⁻,citrate, tartrate, malate, fumarate, formate, or acetate.

It will be appreciated by those skilled in the art that a compound ofthe invention comprising a counterion can be converted to a compound ofthe invention comprising a different counterion. Such a conversion canbe accomplished using a variety of well known techniques and materialsincluding but not limited to ion exchange resins, ion exchangechromatography and selective crystallization.

The compounds of formula I can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humanpatient in a variety of forms adapted to the chosen route ofadministration, i.e., orally or parenterally, by intravenous,intramuscular, topical or subcutaneous routes.

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent, excipient or an assimilable edible carrier. Theymay be enclosed in hard or soft shell gelatin capsules, may becompressed into tablets, or may be incorporated directly with the foodof the patient's diet. For oral therapeutic administration, the activecompound may be combined with one or more excipients and used in theform of ingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers, and the like. Such compositions andpreparations should contain at least 0.1% of active compound. Thepercentage of the compositions and preparations may, of course, bevaried and may conveniently be between about 2 to about 90% of theweight of a given unit dosage form. The amount of active compound insuch therapeutically useful compositions is such that an effectivedosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations, particles, anddevices.

The active compound may also be administered intravenously orintramuscularly by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and the freeze drying techniques, which yield a powderof the active ingredient plus any additional desired ingredient presentin the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina, nanoparticles, and thelike. Useful liquid carriers include water, alcohols or glycols orwater-alcohol/glycol blends, in which the present compounds can bedissolved or dispersed at effective levels, optionally with the aid ofnon-toxic surfactants. Adjuvants such as fragrances and additionalantimicrobial agents can be added to optimize the properties for a givenuse. The resultant liquid compositions can be applied from absorbentpads, used to impregnate bandages and other dressings, or sprayed ontothe affected area using pump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Useful dosages of the compounds of formula I can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

The amount of the compound, or an active salt or derivative thereof,required for use in treatment will vary not only with the particularsalt selected but also with the route of administration, the nature ofthe condition being treated and the age and condition of the patient andwill be ultimately at the discretion of the attendant physician orclinician.

In general, however, a suitable dose will be in the range of from about0.1 to about 500 mg/kg, e.g., from about 0.5 to about 400 mg/kg of bodyweight per day, such as 1 to about 250 mg per kilogram body weight ofthe recipient per day.

The compound is conveniently formulated in unit dosage form; forexample, containing 0.5 to 500 mg, 1 to 400 mg, or 0.5 to 100 mg ofactive ingredient per unit dosage form. In one embodiment, the inventionprovides a composition comprising a compound of the invention formulatedin such a unit dosage form.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations.

The impact of a compound of the invention on the dynamics of bacterialFtsZ polymerization can be determined using a method like Test Adescribed below.

Test A. FtsZ Polymerization Assay.

Compound-induced alteration in the dynamics of FtsZ polymerization canbe tested using a turbidity assay with purified FtsZ protein. Uponaddition of GTP, FtsZ self-associates to form polymeric structures thatscatter light at 340 nm to a greater extent than the monomeric protein.The impact of the compounds of the invention on the polymerizationdynamics of FtsZ can be detected by an increase or decrease in theextent of GTP-induced light scattering (as determined by correspondingchanges in optical density at 340 nm) relative to that observed in theabsence of compound. Quantitation of the overall extent of lightscattering as a function of compound concentration provides anindication of the potency of that compound at altering the dynamics ofFtsZ polymerization.

The impact of a compound of the invention on FtsZ Z-ring formation inbacteria can be determined using a method like Test B described below.

Test B. FtsZ Z-Ring Assay.

The impact of a compound on FtsZ Z-ring formation can be determinedusing a strain of Bacillus subtilis (FG347) that expresses a greenfluorescent protein (GFP)-ZapA fusion protein upon induction withxylose. ZapA is known to associate with FtsZ Z-rings in B. subtilis and,thus, serves as a marker for Z-ring formation. In this assay, log-phaseFG347 bacteria are treated with differing concentrations of compound fortime periods ranging from 1 to 6 hours. At each time point, aliquots aretaken from each culture and then viewed with a fluorescence microscope.In the absence of compound, the bacteria exhibit green fluorescent foci(Z-rings) localized at mid-cell. By contrast, bacteria treated with acompound that disrupts Z-ring formation do not exhibit the greenfluorescent Z-rings at mid-cell and are typically associated with anelongated, filamentous phenotype.

The antibacterial activity of a compound of the invention can bedetermined using a method like Test C described below.

Test C. Antibacterial Assay.

Antibacterial activity can be determined as per Clinical and LaboratoryStandards Institute (CLSI) guidelines using a broth microdilution assayin which log-phase bacteria are grown at 37° C. in appropriate mediumcontaining two-fold serial dilutions of a compound to yield finalconcentrations ranging from 256 to 0.06 μg/mL. For determination ofminimal inhibitory concentration (MIC) values, bacterial growth ismonitored after 24 to 48 hours by measuring optical density at 600 nm.MIC values reflect the minimal compound concentrations at whichbacterial growth is completely inhibited.

Using a procedure similar to Test C, representative compounds of theinvention were tested against methicillin-susceptible Staphylococcusaureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA).Results are shown in Table 1.

TABLE 1 Minimal Inhibitory Concentrations against MSSA and MRSA forrepresentative compounds of the Invention MSSA (MIC MRSA (MIC Example #STRUCTURE ug/ml) ug/ml)* Example 1

2.0 8.0 Example 2

2.0 4.0 Example 3

0.25 0.25 Example 4

0.5 1.0 Example 5

0.5 1.0 Example 6

0.5 1.0 Example 7

2.0 2.0 Example 8

4.0 4.0 Example 9

4.0 4.0 Example 10

2.0 2.0 Example 11

1.0 2.0 Example 12

2.0 4.0 Example 13

32 64 Example 14

32 64 Example 15

>64 >64 Example 16

8.0 64 Example 17

4.0 8.0 Example 18

>64 >64 Example 19

16 n/d Example 20

4.0 n/d Example 21

2.0 2.0 Example 22

4.0 8.0 *n/d = not determined

Representative compounds of the invention were also tested againstvancomycin-resistant Enterococcus faecalis and Enterococcus faecium(VRE), vancomycin-sensitive Enterococcus faecalis and Enterococcusfaecium (VSE). Streptococcus pyogenes, Streptococcus agalactiae,Clostridium difficile, Propionibacterium acnes, Bacillus subtilis, andEscherichia coli, and they were found to have significant antibacterialactivity.

The invention will now be illustrated by the following non-limitingExamples.

EXAMPLES General Methods

Column chromatography refers to flash chromatography conducted ondisposable normal phase Teledyne ISCO column using CombiFlash RfTeledyne ISCO using the solvent systems indicated. Proton (¹H NMR) andcarbon (¹³C NMR) nuclear magnetic resonance were recorded using eitherBruker 400 MHz or Varian 300 MHz Unity Inova spectrometer in thedeuterated solvent indicated with chemical shifts reported in δ unitsdownfield from tetramethylsilane (TMS). Coupling constants are reportedin hertz (Hz). Starting materials and reagents were purchased fromAldrich. Solvents were purchased from Fisher Scientific, and were A.C.S.grade or HPLC grade. Methylene chloride was freshly distilled fromcalcium hydride. All other solvents were used as provided withoutfurther purification.

Example 1 Preparation of Compound 1

A solution of 2-phenylquinoxaline 1a (75 mg, 0.363 mmol) in iodomethane(2.5 mL) in a sealed vial was stirred at 80° C. overnight. After cooledto room temperature, Et₂O was added to the suspension. The solid wascollected by filtration to afford the desired compound (61 mg, 48%) as ared solid. ¹H NMR (DMSO-d₆, 300 MHz) δ 10.29 (s, 1H), 8.62-8.53 (m, 2H),8.43-8.40 (m, 2H), 8.31-8.28 (m, 2H), 7.75-7.72 (m, 3H), 4.79 (s, 3H).

The requisite intermediate was prepared as follows:

a. Preparation of Compound 1a

A microwave tube equipped with a magnetic stirrer, was charged withquinoxalin-2-yl trifluoromethanesulfonate (128 mg, 0.46 mmol),phenylboronic acid (150 mg, 1.23 mmol), dioxane (3.0 ml), Cs₂CO₃ (500mg) and Pd(PPh₃)₂Cl₂ (30 mg). The resulting solution was irradiated for15 min. After cooled to room temperature, the reaction mixture wasdiluted with EtOAc and washed with saturated NaHCO₃, dried over Na₂SO₄.The organic layer was concentrated under reduced pressure and purifiedon silica gel. Elution with EtOAc/hexanes solvent system afforded thedesired compound as a white solid (88 mg, 92% yield). ¹H NMR (CDCl₃, 400MHz) δ 9.26 (s, 1H), 8.14-8.04 (m, 4H), 7.73-7.66 (m, 2H), 7.55-7.44 (m,3H).

Example 2 Preparation of Compound 2

A solution of 2-(3-fluorophenyl)quioxaline 2a (30 mg, 0.08 mmol) iniodomethane (1.0 mL) in a sealed 2-dram vial was stirred at 80° C.overnight. After cooled to room temperature, Et₂O was added to thesuspension. The solid was collected by filtration to afford the desiredcompound (35 mg, 85%) as an orange solid. ¹H NMR (300 MHz, DMSO-d₆) δ10.33 (s, 1H), 8.64-8.54 (m, 2H), 8.35-8.21 (m, 4H), 7.83-7.76 (m, 1H),7.62-7.57 (m, 1H), 4.78 (s, 3H).

The requisite intermediate was prepared as follows:

a. Preparation of Compound 2a

A 25-mL round bottom flask equipped with a magnetic stirrer, a condenserand a nitrogen in/outlet adapter was charged with 2-bromoquinoxaline(100 mg, 0.48 mmol), 4-Fluorophenylboronic acid (80 mg, 0.57 mmol),water/dioxane (1.0 mL/4.0 ml), K₂CO₃ (132 mg, 0.96 mmol). The resultingsolution was degassed for 15 min, then Pd(PPh₃)₄ (27 mg, 0.024 mmol) wasadded. The reaction mixture was warmed to 100° C. and stirred for 1 h.After cooled to room temperature, the reaction mixture was diluted withEtOAc and washed with saturated NaHCO₃, brine, dried over Na₂SO₄. Theorganic layer was concentrated under reduced pressure and purified onsilica gel. Elution with EtOAc/hexanes solvent system afforded thedesired compound (40 mg, 38% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.34 (s,1H), 8.18 (m, 2H), 8.00 (m, 2H), 7.82 (m, 2H), 7.57 (m, 1H), 7.25 (m,1H).

Example 3 Preparation of Compound 3

A solution of the 2-([1,1′-biphenyl]-3-yl)quinoxaline 3a (100 mg, 0.354mmol) in iodomethane (3.0 mL) in a sealed vial was stirred at 80° C.overnight. After cooled to room temperature, Et₂O was added to thesuspension. The solid was collected by filtration to afford the desiredcompound (81 mg, 54%) as an orange solid. ¹H NMR (300 MHz, CD₃OD) δ10.21 (s, 1H), 8.58 (s, 1H), 8.52-8.49 (m, 2H), 8.32 (d, J=8.0 Hz, 1H),8.20 (m, 2H), 7.87 (d, J=6.0 Hz, 1H), 7.71-7.66 (m, 3H), 7.44 (m, 2H),7.36 (m, 1H), 4.85 (s, 3H).

The requisite intermediate was prepared as follows:

a. Preparation of Compound 3a

A microwave tube equipped with a magnetic stirrer, was charged withquinoxalin-2-yl trifluoromethanesulfonate (175 mg, 0.63 mmol),3-biphenylboronic acid (200 mg, 1.0 mmol), dioxane (3.0 ml), Cs₂CO₃ (500mg) and Pd(PPh₃)₂Cl₂ (30 mg). The resulting solution was irradiated at120° C. for 15 min. After cooled to room temperature, the reactionmixture was diluted with EtOAc and washed with saturated NaHCO₃, driedover Na₂SO₄. The organic layer was concentrated under reduced pressureand purified on silica gel. Elution with EtOAc/hexanes solvent systemafforded the desired compound as a white solid (150 mg, 85% yield). ¹HNMR (400 MHz, CDCl₃) δ 9.39 (s, 1H), 8.43 (s, 1H), 8.20-8.13 (m, 3H),7.81-7.70 (m, 4H), 7.65 (t, J=4.0 Hz, 2H), 7.50 (t, J=4.0 Hz, 2H), 7.39(t, J=4.0 Hz, 1H).

Example 4 Preparation of Compound 4

A solution of the 2-(3-(tert-butyl)phenyl)quinoxaline 4a (70 mg, 0.267mmol) in iodomethane (2.0 mL) in a sealed vial was stirred at 80° C.overnight. After cooled to room temperature, Et₂O was added to thesuspension. The solid was collected by filtration to afford the desiredcompound (52 mg, 48%) as yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.27(s, 1H), 8.63-8.54 (m, 2H), 8.40 (s, 1H), 8.31-8.27 (m, 2H), 8.23 (d,J=8.0 Hz, 1H), 7.76 (m, 1H), 7.66 (m, 1H), 4.80 (s, 3H), 1.43 (s, 9H).

The requisite intermediate was prepared as follows:

a. Preparation of Compound 4a

A microwave tube equipped with a magnetic stirrer, was charged withquinoxalin-2-yl trifluoromethanesulfonate (165 mg, 0.59 mmol),3-tert-butylphenylboronic acid (200 mg, 1.12 mmol), dioxane (3.0 ml),Cs₂CO₃ (500 mg) and Pd(PPh₃)₂Cl₂ (30 mg). The resulting solution wasirradiated at 120° C. for 15 min. After cooled to room temperature, thereaction mixture was diluted with EtOAc and washed with saturatedNaHCO₃, dried over Na₂SO₄. The organic layer was concentrated underreduced pressure and purified on silica gel. Elution with EtOAc/hexanessolvent system afforded the desired compound as a white solid (145 mg,93% yield). ¹H NMR (300 MHz, CDCl₃) δ 9.32 (s, 1H), 8.23-8.17 (m, 3H),7.97 (dt, J=7.5 Hz, 1H), 7.82-7.72 (m, 2H), 7.6-7.48 (m, 2H), 1.43 (s,9H).

Example 5 Preparation of Compound 5

A solution of the 2-(4-(tert-butyl)phenyl)quinoxaline 5a (80 mg, 0.305mmol) in iodomethane (3.0 mL) in a sealed vial was stirred at 80° C.overnight. After cooled to room temperature, Et₂O was added to thesuspension. The solid was collected by filtration to afford the desiredcompound (69 mg, 56%) as a red solid. ¹H NMR (300 MHz, CD₃OD) δ 10.10(s, 1H), 8.57 (m, 2H), 8.41 (d, J=6.6 Hz, 2H), 8.30-8.27 (m, 2H), 7.76(d, J=8.4 Hz, 2H), 4.82 (s, 3H), 1.42 (s, 9H).

The requisite intermediate was prepared as follows:

a. Preparation of Compound 5a

A microwave tube equipped with a magnetic stirrer, was charged withquinoxalin-2-yl trifluoromethanesulfonate (165 mg, 0.59 mmol),3-tert-butylphenylboronic acid (200 mg, 1.12 mmol), dioxane (3.0 ml),Cs₂CO₃ (500 mg) and Pd(PPh₃)₂Cl₂ (30 mg). The resulting solution wasirradiated at 120° C. for 15 min. After cooled to room temperature, thereaction mixture was diluted with EtOAc and washed with saturatedNaHCO₃, dried over Na₂SO₄. The organic layer was concentrated underreduced pressure and purified on silica gel. Elution with EtOAc/hexanessolvent system afforded the desired compound as a white solid (130 mg,83% yield). ¹H NMR (300 MHz, CDCl₃) δ 9.32 (s, 1H), 8.12-8.09 (m, 4H),7.81-7.71 (m, 2H), 7.59 (d, J=6.6 Hz, 2H), 1.39 (s, 9H).

Example 6 Preparation of Compound 6

A solution of the substituted ester 6c (15 mg, 0.038 mmol) iniodomethane (1.5 mL) in a sealed 2-dram vial was stirred at 90° C.overnight. After cooled to room temperature, Et₂O was added to thesuspension. The solid was collected by filtration to afford the desiredcompound (10 mg, 50%) as a light brown solid. ¹H NMR (300 MHz, DMSO-d₆)δ 10.48 (s, 1H), 8.93 (t, J=1.5 Hz, 1H), 8.88 (t, J=1.6 Hz, 1H),8.65-8.63 (m, 2H), 8.45 (t, J=1.5 Hz, 1H), 8.35-4.31 (m, 2H), 7.81 (d,J=8.4 Hz, 2H), 7.62 (d, J=8.4 hz, 2H), 4.82 (s, 3H), 3.98 (s, 3H), 1.36(s, 9H).

The requisite intermediates were prepared as follows:

a. Preparation of Compound 6a

A 100-mL round bottom flask equipped with a magnetic stirrer, acondenser and a nitrogen in/outlet adapter was charged with commerciallyavailable methyl 3-bromo-5-iodobenzoate (2.83 g, 8.3 mmol),4-tert-butylphenylboronic acid (1.64 g, 9.2 mmol), water/dioxane (10mL/30 ml), K₂CO₃ (2.3 g, 16.6 mmol). The resulting solution was degassedfor 15 min, then Pd(PPh₃)₄ (340 mg) was added. The reaction mixture waswarmed to 100° C. and stirred for 3 h. After cooled to room temperature,the reaction mixture was diluted with EtOAc (100 mL) and washed withsaturated NaHCO₃ (30 mL), brine (30 mL), dried over Na₂SO₄. The organiclayer was concentrated under reduced pressure and purified on silicagel. Elution with EtOAc/hexanes solvent system afforded the desiredcompound (1.69 g, 58% yield). ¹H NMR (300 MHz, CDCl₃) δ 8.19 (a, 1H),8.12 (s, 1H), 7.91 (s, 1H), 7.52 (m, 4H), 3.95 (s, 3H), 1.38 (s, 9H).

b. Preparation of Compound 6b

To a solution of 6a (400 mg, 1.15 mmol), in 5.0 mL dioxane was addedKOAc (332 mg, 3.45 mmol), diborane (322 mg, 1.27 mmol) followed byPd(dppf)Cl₂. The mixture was heated at 80° C. for 16 h. The reactionmixture was cooled to room temperature, the solids were filtered off,the solvent was removed and the crude product was purfied in ISCO using10% EtOAc in hexane to afford the desired product (300 mg, 66% yield).¹H NMR (300 MHz, CDCl₃) δ 8.42 (s, 1H), 8.37 (s, 1H), 8.22 (s, 1H), 7.61(d, J=8.7 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 3.94 (s, 3H), 1.36 (s, 21H).

c. Preparation of Compound 6c

A 25-mL round bottom flask equipped with a magnetic stirrer, a condenserand a nitrogen in/outlet adapter was charged with 2-bromoquinoxaline (13mg, 0.063 mmol), boronate ester 6b (25 mg, 0.063 mmol), water/dioxane(1.0 mL/4.0 ml), K₂CO₃ (17 mg, 0.126 mmol). The resulting solution wasdegassed for 15 min, then Pd(PPh₃)₄ (5 mg) was added. The reactionmixture was warmed to 100° C. and stirred for 1 h. After cooled to roomtemperature, the reaction mixture was diluted with EtOAc and washed withsaturated NaHCO₃, brine, dried over Na₂SO₄. The organic layer wasconcentrated under reduced pressure and purified on silica gel. Elutionwith 10% EtOAc/hexanes solvent system afforded the desired compound (15mg, 60% yield). ¹H NMR (300 MHz, CDCl₃) δ 9.46 (s, 1H), 8.83 (s, 1H),8.69 (m, 1H), 8.46 (s, 1H), 8.21 (m, 2H), 7.86 (m, 2H), 7.72 (d, J=12.0Hz, 2H), 7.58 (d, J=12.0 Hz, 2H), 4.05 (s, 3H), 1.42 (s, 9H).

Example 7 Preparation of Compound 7

A solution of the amide 7b (12 mg, 0.031 mmol) in iodomethane (1.0 mL)in a sealed 2-dram vial was stirred at 60° C. overnight. After cooled toroom temperature, Et₂O was added to the suspension. The solid wascollected by filtration to afford the desired compound (14 mg, 85%) as ayellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.44 (s, 1H), 8.89 (s, 1H),8.72 (s, 1H), 8.46 (s, 1H), 8.32 (m, 4H), 7.85 (d, J=6.6 Hz, 2H), 7.61(d, J=6.6 Hz, 2H), 4.82 (s, 3H), 1.37 (s, 9H).

The requisite intermediates were prepared as follows:

a. Preparation of Compound 7a

To a solution of the ester 6c (90 mg, 0.23 mmol) in THF:H₂O (4.0 ml:2.0ml) was added LiOH.H₂O (50 mg) and the mixture was stirred at 50° C.overnight. The organic solvent was removed and the aqueous portion wasadjusted to pH2 by addition of 2N HCl. The white solid thus formed wascollected by filtration. Air drying of the solid provided the desiredproduct as a white solid (74 mg, 84% yield) which was used for the nextstep without further purification.

b. Preparation of Compound 7b

To a suspension of the acid 7a (25 mg, 0.065 mmol) in 2.0 mL of DCM wasadded 4 drops of oxalyl chloride and one drop of DMF and the mixture wasstirred at room temperature. After 1 h, the solvent was removed and theresidue was dissolved in DCM. The DCM solution was added to NH₃.H₂O (1.0mL) at 0° C. The mixture was stirred at room temperature for 1 h. TheDCM layer was separated and dried over Na₂SO₄. The solvent wasconcentrated and was purified using 70% ethyl acetate in hexane toafford the desired compound as a white solid (12 mg, 48% yield). ¹H NMR(300 MHz, CDCl₃) δ 9.43 (s, 1H), 8.60 (m, 1H), 8.56 (m, 1H), 8.20-8.14(m, 3H), 7.80 (m, 2H), 7.77 (d, J=6.0 Hz, 2H), 7.54 (d, J=6.0 Hz, 2H),1.39 (s, 9H).

Example 8 Preparation of Compound 8

A solution of the amide 8a (15 mg, 0.035 mmol) in iodomethane (1.0 mL)in a sealed 2-dram vial was stirred at 70° C. overnight. After cooled toroom temperature, Et₂O was added to the suspension. The solid wascollected by filtration to afford the desired compound (20 mg, 100%) asa yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 11.26 (s, 1H), 9.04 (s, 1H),8.74 (s, 1H), 8.48 (m, 1H), 8.31-8.18 (m, 4H), 7.60 (d, J=8.4 Hz, 2H),7.47 (d, J=8.4 Hz, 2H), 5.08 (s, 3H), 3.84 (m, 2H), 3.56 (m, 2H), 1.38(s, 9H).

The requisite intermediates were prepared as follows:

a. Preparation of Compound 8a

To a suspension of the acid 7a (25 mg, 0.065 mmol) in 3.0 mL of DCM wasadded 4 drops of oxalyl chloride and one drop of DMF and the mixture wasstirred at room temperature. After 1 h, the solvent was removed and theresidue was dissolved in DCM. The DCM solution was added to ethanolamine(40 mg in 1.0 ml of DCM) and 4 drops of TEA at −78° C. The mixture wasgradually warm to room temperature for 1 h. The DCM layer was washedwith NaHCO₃ and dried over Na₂SO₄. The solvent was concentrated and waspurified using 100% ethyl acetate to afford the desired compound as anorange solid (19 mg, 70% yield). ¹H NMR (300 MHz, CDCl₃) δ 9.30 (s, 1H),8.44 (d, J=12.0 Hz, 2H), 8.10-8.06 (m, 3H), 7.77-7.70 (m, 2H), 7.56-7.47(m, 4H), 7.22 (m, 1H), 3.92 (m, 2H), 3.73 (m, 2H), 1.39 (s, 9H).

Example 9 Preparation of Compound 9

To a suspension of the acid 7a (25 mg, 0.065 mmol) in 3.0 mL of DCM wasadded 4 drops of oxalyl chloride and one drop of DMF and the mixture wasstirred at room temperature. After 1 h, the solvent was removed and theresidue was dissolved in DCM. The DCM solution was added to ethylenediamine (25 mg in 1.0 ml of DCM). The mixture was stirred at roomtemperature for 1 h. The DCM layer was washed with NaHCO₃ and dried overNa₂SO₄. The solvent was concentrated and was purified using10/89/1:MeOH/CHCl₃/ammonium hydroxide to afford the desired compound asa white foam (18 mg, 70% yield). ¹H NMR (300 MHz, CDCl₃) δ 9.41 (s, 1H),8.54 (d, J=12.0 Hz, 1H), 8.18-8.12 (m, 2H), 7.83-7.74 (m, 2H), 7.76 (d,J=12.0 Hz, 2H), 7.51 (d, J=12.0 Hz, 2H), 7.11 (m, 1H), 3.59 (m, 2H),3.02 (m, 2H), 1.71 (bs, 3H), 1.32 (s, 9H).

Example 10 Preparation of Compound 10

To a 10-mL vial was added di-tert-butyl guanidine compound 10d (20 mg,0.037 mmol), CH₂Cl₂ (1.0 mL), and TFA (1.0 mL). The sealed vial wasstirred at rt overnight. The solvent was removed and the residue waspurified on silica gel. Elution with CH₂Cl₂ to(10/89/1:MeOH/CHCl₃/ammonium hydroxide) afforded the title compound as awhite solid (6.5 mg, 53% yield).

The requisite intermediates were prepared as follows:

a. Preparation of Compound 10a

The compound was prepared using a procedure similar to the proceduredescribed by William C. Lumma, Jr., et al., Journal of MedicinalChemistry, 1981, 24(1), 93-101.

b. Preparation of Compound 10b

A microwave tube equipped with a magnetic stirrer, was charged with2-chloro-5-methylquinoxaline 10a (100 mg, 0.56 mmol),4-tert-butylphenylboronic acid (150 mg, 0.84 mmol), dioxane (3.0 ml),Cs₂CO₃ (400 mg) and Pd(PPh₃)₂Cl₂ (30 mg). The resulting solution wasirradiated at 120° C. for 15 min. After cooled to room temperature, thereaction mixture was diluted with EtOAc and washed with saturatedNaHCO₃, dried over Na₂SO₄. The organic layer was concentrated underreduced pressure and purified on silica gel. Elution with EtOAc/hexanessolvent system afforded the desired compound as a white solid (80 mg,52% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.25 (s, 1H), 8.06 (d, J=8.0 Hz,2H), 7.92 (d, J=8.0 Hz, 1H), 7.59 (t, J=8.0 Hz, 1H), 7.54-7.49 (m, 3H),2.76 (s, 3H), 1.32 (s, 9H).

c. Preparation of Compound 10c

A mixture of substituted quinoxaline 10b (77 mg, 0.28 mmol), NBS (68 mg,0.385 mmol) in carbon tetrachloride (4.0 mL) was heated under light for90 minutes. The solids were filtered and the solvent was removed to givethe crude product. Purification using 10% ethyl acetate in hexaneafforded the product (100 mg, yield) with a mixture with dibrominatedproduct (1:1). The mixture was used for the next step without furtherseparation.

d. Preparation of Compound 10d

A 25-mL round bottom flask equipped with a magnetic stirrer, a condenserand a nitrogen in/outlet adapter was charged with above mixture 10c (30mg), DMF (2 mL), K₂CO₃ (60 mg, 0.44 mmol), and1,3-bis(tert-butoxycarbonyl)guanidine (50 mg, 0.19 mmol) The reactionmixture was stirred at 50° C. for 2 h. The reaction mixture was dilutedwith EtOAc, washed with water, 10% LiCl, brine, dried over Na₂SO₄,concentrated, and purified on silica gel. Elution with 20% EtOAc/hexanesafforded the title compound as a white solid (20 mg). ¹H NMR (400 MHz,CDCl₃) δ 9.45 (bs, 2H), 9.23 (s, 1H), 8.08 (d, J=8.4 Hz, 2H), 7.95 (d,J=8.3 Hz, 1H), 7.64 (t, J=7.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H), 7.36 (d,J=7.2 Hz, 1H), 5.87 (s, 2H), 1.37 (s, 9H), 1.32 (s, 9H), 1.05 (s, 9H).

Example 11 Preparation of Compound 11

A 10-mL vial was added di-tert-butyl guanidine compound 11c (80 mg, 0.15mmol), CH₂Cl₂ (1.0 mL), and TFA (1.0 mL). The sealed vial was stirred atrt overnight. The solvent was removed and the residue was purified onsilica gel. Elution with CH₂Cl₂ to (10/89/1:MeOH/CHCl₃/ammoniumhydroxide) afforded the title compound as white solid (40 mg, 80%yield). ¹H NMR (300 MHz, CD₃OD) δ 9.51 (s, 1H), 8.36 (t, J=1.8 Hz, 1H),8.19 (dd, J=8.4, 1.8 Hz, 1H), 8.10-8.06 (m, 1H), 7.93-7.82 (m, 2H),7.69-7.65 (m, 1H), 7.56 (t, J=7.5 hz, 1H), 5.06 (s, 2H), 1.46 (s, 9H).

The requisite intermediates were prepared as follows:

a. Preparation of Compound 11a

A microwave tube equipped with a magnetic stirrer, was charged with2-chloro-5-methylquinoxaline 10a (340 mg, 1.90 mmol),3-tert-butylphenylboronic acid (605 mg, 3.4 mmol), dioxane (3.5 ml),Cs₂CO₃ (800 mg) and Pd(PPh₃)₂Cl₂ (80 mg). The resulting solution wasirradiated at 120° C. for 15 min. After cooled to room temperature, thereaction mixture was diluted with EtOAc and washed with saturatedNaHCO₃, dried over Na₂SO₄. The organic layer was concentrated underreduced pressure and purified on silica gel. Elution with EtOAc/hexanessolvent system afforded the desired compound as a white solid (150 mg,28% yield). ¹H NMR (300 MHz, CDCl₃) δ 9.32 (s, 1H), 8.22 (s, 1H),8.03-7.95 (m, 2H), 7.67-7.50 (m, 4H), 2.83 (s, 3H), 1.42 (s, 9H).

b. Preparation of Compound 11b

A mixture of substituted quinoxaline 11a (120 mg, 0.43 mmol), NBS (116mg, 0.65 mmol) in carbon tetrachloride (4.0 mL) was heated under lightfor 60 minutes. The solids were filtered and the solvent was removed togive the crude product. Purification using 10% ethyl acetate in hexaneafforded the product (100 mg, 66% yield). NMR (300 MHz, CDCl₃) δ: 9.44(s, 1H), 8.26-8.17 (m, 2H), 8.03-7.75 (m, 4H), 7.61 (m, 2H), 5.25 (s,2H), 1.46 (s, 9H).

c. Preparation of Compound 11c

A 25-mL round bottom flask equipped with a magnetic stirrer, a condenserand a nitrogen in/outlet adapter was charged with above bromide 11b (90mg, 0.254 mmol), DMF (3.0 mL), K₂CO₃ (70 mg, 0.5 mmol), and1,3-bis(tert-butoxycarbonyl)guanidine (150 mg, 0.57 mmol) The reactionmixture was stirred at 50° C. for 12 h. The reaction mixture was dilutedwith EtOAc, washed with water, 10% LiCl, brine, dried over Na₂SO₄,concentrated, and purified on silica gel. Elution with 10% EtOAc/hexanesafforded the title compound as a white solid (100 mg, 74% yield). ¹H NMR(CDCl₃, 400 MHz) δ 9.5 (bs, 2H), 9.31 (s, 1H), 8.25 (s, 1H), 8.06-7.98(m, 2H), 7.25 (m, 1H), 7.59-7.43 (m, 3H), 5.94 (s, 2H), 1.44-1.13(3×9H).

Example 12 Preparation of Compound 12

To a 10-mL vial was added di-tert-butyl guanidine compound 12e (39 mg,0.073 mmol), CH₂Cl₂ (1.0 mL), and TFA (1.0 mL). The sealed vial wasstirred at rt overnight. The solvent was removed and the residue waspurified on silica gel. Elution with CH₂Cl₂ to(10/89/1:MeOH/CHCl₃/ammonium hydroxide) afforded the title compound aswhite solid (17 mg, 70% yield). ¹HNMR (400 MHz, CD₃OD) δ 9.33 (s, 1H),8.18 (d, J=8.3 Hz, 1H), 8.02 (d, J=6.8 Hz, 1H), 7.74-7.67 (m, 5H), 5.00(s, 2H), 1.42 (s, 9H).

The requisite intermediates were prepared as follows:

a. Preparation of Compound 12a

Prepared as described in the literature—European Journal of MedicinalChemistry, 50, 264-273, 2012.

b. Preparation of Compound 12b

To a solution of 8-methylquinazolin-4(3H)-one 12a (1.1 g, 6.92 mmol) in155 ml ACN was added 10.1 mL POCl₃. The reaction mixture is refluxeduntil completion, cooled to room temperature. The solvent was removedunder vacuum, and the crude product was purified in ISCO using Ethylacetate:hexane solvent system to afford the pure product (430 mg, 35%yield). ¹H NMR (CDCl₃, 400 MHz) δ 9.06 (s, 1-H), 8.12 (d, J=8.4 Hz, 1H),7.80 (d, J=6.9 Hz, 1-H), 7.61 (m, 1H), 2.78 (s, 3H).

c. Preparation of Compound 12c

A 50-mL round bottom flask equipped with a magnetic stirrer, a condenserand a nitrogen in/outlet adapter was charged with4-chloro-8-methylquinazoline 12b (200 mg, 1.12 mmol),4-tert-butylphenylboronic acid (300 mg, 1.68 mmol), DME (12 mL), Na₂CO₃(5.0 ml)(2M). The resulting solution was degassed for 15 min, thenPd(PPh₃)₄ (130 mg, 0.112 mmol) was added. The reaction mixture waswarmed to 85° C. and stirred for 1 h. After cooled to room temperature,the reaction mixture was diluted with EtOAc and washed with saturatedNaHCO₃, brine, dried over Na₂SO₄. The organic layer was concentratedunder reduced pressure and purified on silica gel. Elution withEtOAc/hexanes solvent system afforded the title compound (210 mg, 67%yield). ¹H NMR (CDCl₃, 400 MHz) δ 9.39 (s, 1H), 8.02 (d, J=8.4 Hz, 1H),7.72 (m, 3H), 7.57 (d, J=8.0 Hz, 2H), 7.54 (m, 1H), 2.83 (s, 3H), 1.39(s, 9H).

d. Preparation of Compound 12d

A mixture of 4-(4-tert-butyl)phenyl)-8-methylquinazoline 12c (210 mg,0.76 mmol), NBS (151 mg, 0.84 mmol) in carbon tetrachloride (10.0 mL)was heated under light for 1 h. The solids were filtered and the solventwas removed to give the crude product. Purification using 10% ethylacetate in hexane afforded the product (163 mg, 60% yield) along withsome dibrominated product (40 mg). ¹H NMR (400 MHz, CDCl₃) δ 9.44 (s,1H), 8.16 (dd, J=8.0, 1.2 Hz, 1H), 8.00 (dd, J=7.2, 1.2 Hz, 1H), 7.70(m, 3H), 5.20 (s, 2H), 1.39 (s, 9H).

e. Preparation of Compound 12e

A 10-mL round bottom flask equipped with a magnetic stirrer, a condenserand a nitrogen in/outlet adapter was charged with8-(bromomethyl)-4-(4-(tert-butyl)phenyl)quinazoline 12d (34 mg, 0.096mmol), DMF (1.0 mL), K₂CO₃ (27 mg, 0.19 mmol), and1,3-bis(tert-butoxycarbonyl)guanidine (30 mg, 0.116 mmol) The reactionmixture was stirred at 50° C. for 16 h. The reaction mixture was dilutedwith EtOAc, washed with water, 10% LiCl, brine, dried over Na₂SO₄,concentrated, and purified on silica gel. Elution with EtOAc/hexanesafforded the title compound as a white solid (39 mg, 76% yield). ¹H NMR(400 MHz, CDCl₃) δ 9.45 (bs, 2H), 9.34 (s, 1H), 8.06 (d, J=7.3 Hz, 1H),7.73 (d, J=8.0 Hz, 2H), 7.60-7.51 (m, 4H), 5.93 (s, 2H), 1.43 (s, 9H),1.40 (s, 9H), 1.17 (s, 9H).

Example 13 Preparation of Compound 13

To a mixture of bromide 12d (34.3 mg, 0.096 mmol), K₂CO₃ (27 mg, 0.19mmol) in 1.0 mL DMF was added acetamidine HCl (11 mg, 0.116 mmol) andthe resulting mixture was stirred at room temperature for 16 h. Thesolvent was removed under vacuum and the resulting residue was purifiedin ISCO eluting with CH₂Cl₂ to (10/89/1:MeOH/CHCl₃/ammonium hydroxide)which afforded the mono substituted product as white solid (4 mg). ¹HNMR (400 MHz, CD₃OD) δ 9.34 (s, 1H), 8.23 (d, J=8.5 Hz, 1H), 8.05 (d,J=8.0 Hz, 1H), 7.75-7.68 (m, 5H), 5.09 (s, 2H), 2.28 (s, 3H), 1.43 (s,9H).

Example 14 Preparation of Compound 14

To a solution of azide 14a (23 mg, 0.072 mmol) in 1.8 mL THF and 0.2 mLH₂O was added polymer supported PPh₃ (116 mg) and the mixture wasstirred for 16 h. The solid was filtered off and the solvents wereremoved under vacuuo. The resulting residue was dissolved in MeOH andwas purified in ISCO eluting with CH₂Cl₂ to (10/89/1:MeOH/CHCl₃/ammoniumhydroxide) which afforded the title compound as white solid (14 mg, 66%yield). ¹H NMR (400 MHz, CD₃OD) δ 9.29 (s, 1H), 8.09 (dd, J=8.5, 1.2 Hz,1H), 7.97 (d, J=6.6 Hz, 1H), 7.72-7.64 (m, 5H), 4.42 (s, 2H), 1.42 (s,9H).

The requisite intermediate was prepared as follows:

a. Preparation of Compound 14a

To a solution of the bromide 12d (25 mg, 0.070 mmol) in 2.5 mL ofacetone was added NaN₃ (5.5 mg, 0.085 mmol) and the reaction mixture wasstirred for 12 h. After the completion of the reaction, the solvent wasremoved, the residue was diluted with ethyl acetate and was washed withNaHCO₃ and brine. Separation in ISCO using Ethyl acetate provided theproduct (21 mg, 94% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.39 (s, 1H), 8.17(dd, J=8.5, 1.2 Hz, 1H), 7.92 (d, J=7.0 Hz, 1H), 7.72 (d, J=8.4 Hz, 2H),7.61-7.58 (m, 3H), 5.06 (s, 2H), 1.40 (s, 9H).

Example 15 Preparation of Compound 15

To a solution of 2-chloro-3-(m-tolyl)quinoxaline 15a (50 mg, 197 mmol)in 2 ml ACN was added excess ethylene diamine (0.1 ml) and the resultingsolution was stirred at room temperature overnight. The solvents wereremoved and the residue was purified in ISCO. Elution with CH₂Cl₂ to(10/89/1:MeOH/CHCl₃/ammonium hydroxide) afforded the desired compound(38 mg, 69% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.93 (d, J=8.1 Hz, 1H),7.74 (d, J=8.1 Hz, 1H), 7.61-7.51 (m, 3H), 7.47-7.33 (m, 3H), 5.62 (bs,1H), 3.64 (qt, 2H), 3.02 (t, J=5.7 Hz, 2H), 2.47 (s, 3H),

The requisite intermediate was prepared as follows:

a. Preparation of Compound 15a

A mixture of commercially available 2,3-dichloroquinoxaline (800 mg, 4.0mm01), 3-methyl phenylboronic acid (880 mg, 4.4 mmol), Cs₂CO₃ (2.5 g),PCy₃ (42 mg) and Pd₂(dba)₃ in dioxane (10 mL) under nitrogen wasrefluxed for 24 hours. After cooled to room temperature, the reactionmixture was diluted with EtOAc (100 mL) and washed with saturated NaHCO₃(30 mL), brine (30 mL), dried over Na₂SO₄. The organic layer wasconcentrated under reduced pressure and purified on silica gel. Elutionwith EtOAc/hexanes solvent system afforded compound 15a (300 mg, 30%yield). ¹H NMR (300 MHz, CDCl₃) δ 8.20-8.16 (m, 1H), 8.11-8.07 (m, 1H),7.85-7.80 (m, 2H), 7.66 (m, 2H), 7.44 (t, J=6.0 Hz, 1H), 7.36 (d, J=7.5Hz, 1H), 2.49 (s, 3H).

Example 16 Preparation of Compound 16

A 10-mL vial was added di-tert-butyl guanidine compound 16e (40 mg,0.075 mmol), CH₂Cl₂ (1.0 mL), and TFA (1.0 mL). The sealed vial wasstirred at rt overnight. The solvent was removed and the residue waspurified on silica gel. Elution with CH₂Cl₂ to(10/89/1:MeOH/CHCl₃/ammonium hydroxide) afforded the title compound aswhite solid (14 mg, 56% yield). ¹HNMR (400 MHz, CDCl₃) δ 9.14 (s, 1H),8.62 (bs, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.65 (m,1H), 7.49 (m, 7H), 4.91 (s, 2H), 1.35 (s, 9H).

The requisite intermediates were prepared as follows:

a. Preparation of Compound 16a

Prepared following a literature method: PCT Int. Appl. 2004014871,February 2004.

b. Preparation of Compound 16b

To a solution of 4-methylquinazolin-8-ol 16a (130 mg, 0.812 mmol), Et₃N(0.17 mL) in 5.0 mL DCM was added Tf₂O (0.16 mL, 0.975 mmol) at −78° C.and the reaction mixture was stirred for 1.5 h. After warming to roomtemperature, the reaction mixture was diluted with DCM, washed withNaHCO₃, dried, and concentrated to give the crude product. Purificationin ISCO using 0-40% ethyl acetate in hexane produced the pure triflate(168 mg, 71% yield). ¹H NMR (CDCl₃, 400 MHz) δ 9.31 (s, 1H), 8.15 (d,J=8.4 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.68 (m, 1H), 3.00 (s, 1H).

c. Preparation of Compound 16c

A 25-mL round bottom flask equipped with a magnetic stirrer, a condenserand a nitrogen in/outlet adapter was charged with triflate 16b (100 mg,0.342 mmol), 4-tert-butylphenylboronic acid (91 mg, 0.511 mmol), DME(4.0 ml), Na₂CO₃ (1.5 mL, 2M). The resulting solution was degassed for15 min, then Pd(PPh₃)₄ (40 mg, 0.034 mmol) was added. The reactionmixture was warmed to 80° C. and stirred for 1 h. After cooled to roomtemperature, the reaction mixture was diluted with EtOAc and washed withsaturated NaHCO₃, brine, dried over Na₂SO₄. The organic layer wasconcentrated under reduced pressure and purified on silica gel. Elutionwith EtOAc/hexanes solvent system afforded the desired compound (86 mg,91% yield). ¹H NMR (CDCl₃, 400 MHz) δ 9.21 (s, 1H), 8.09 (dd, J=8.4, 1.4Hz, 1H), 7.90 (dd, J=7.2, 1.4 Hz, 1H), 7.69-7.64 (m, 1H), 7.63 (d, J=8.0Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 2.99 (s, 3H), 1.38 (s, 9H).

d. Preparation of Compound 16d

A mixture of substituted quinazoline 16c (80 mg, 0.289 mmol), NBS (57mg, 0.319 mmol) in carbon tetrachloride (5.0 mL) was heated under lightfor 1 h. The solids were filtered and the solvent was removed to givethe crude product. Purification using 10% ethyl acetate in hexaneafforded the product (55 mg, 53% yield) with some dibrominated product.¹H NMR (400 MHz, CDCl₃) δ 9.31 (s, 1H), 8.19 (dd, J=8.4, 1.3 Hz, 1H),7.95 (dd, J=7.2, 1.3 Hz, 1H), 7.76 (m, 1H), 7.75 (d, J=8.3 Hz, 2H), 7.53(d, J=8.4 Hz, 2H), 4.97 (s, 2H), 1.39 (s, 9H).

e. Preparation of Compound 16e

A 25-mL round bottom flask equipped with a magnetic stirrer, a condenserand a nitrogen in/outlet adapter was charged with bromomethylintermediate 16d (30 mg, 0.084 mmol), DMF (2.0 mL), K₂CO₃ (23 mg, 0.169mmol), and 1,3-bis(tert-butoxycarbonyl)guanidine (26 mg, 0.10 mmol) Thereaction mixture was stirred at 50° C. for 16 h. The reaction mixturewas diluted with EtOAc, washed with water, 10% LiCl, brine, dried overNa₂SO₄, concentrated, and purified on silica gel. Elution with 50%EtOAc/hexanes afforded the title compound as a white solid (44 mg, 98%yield). ¹H NMR (400 MHz, CDCl₃) δ 9.54 (bs, 2H), 9.25 (s, 1H), 8.05 (dd,J=8.4, 1.3 Hz, 1H), 7.93 (dd, J=7.2, 1.3 Hz, 1H), 7.7 (m, 1H), 7.64 (d,J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 5.94 (s, 2H), 1.42 (s, 9H), 1.38(s, 9H), 1.16 (s, 9H).

Example 17 Preparation of Compound 17

A 10-mL vial was added di-tert-butyl guanidine compound 17e (25 mg,0.047 mmol), CH₂Cl₂ (0.5 mL), and TFA (0.5 mL). The sealed vial wasstirred at rt overnight. The solvent was removed and the residue waspurified on silica gel. Elution with CH₂Cl₂ to(10/89/1:MeOH/CHCl₃/ammonium hydroxide) afforded the desired compound aswhite solid (5 mg, 32% yield). ¹H NMR (300 MHz, CD₃OD) δ 9.04 (d, J=4.5Hz, 1H), 8.95 (d, J=3.9 Hz, 1H), 7.81 (d, J=4.2 Hz, 1H), 7.69 (m, 3H),7.59 (d, J=8.7 Hz, 2H), 5.12 (s, 2H), 1.40 (s, 9H).

The requisite intermediates were prepared as follows:

a. Preparation of Compound 17a

Prepared by following literature method: Journal of the AmericanChemical Society, 131 (2), 763-777, 2009.

b. Preparation of Compound 17b

To a solution of 8-methyl-1,5-napthyridin-4-ol 17a (165 mg, 1.03 mmol),Et₃N (0.21 mL) in 4.0 mL DCM was added Tf₂O (0.210 mL, 1.24 mmol) at 0°C. and the reaction mixture was stirred for 1 h. After warming to roomtemperature, the reaction mixture was diluted with DCM, washed withNaHCO₃, dried, and concentrated to give the crude product. Purificationin ISCO using 10% MeOH in DCM produced the pure triflate (160 mg, 53%yield). ¹H NMR (CDCl₃, 300 MHz) δ 9.03 (d, J=4.8, 1H), 8.94 (d, J=4.5Hz, 1H), 7.60 (d, J=4.2 Hz, 1H), 7.52 (d, J=4.5 Hz, 1H), 2.87 (s, 3H).

c. Preparation of Compound 17c

A 25-mL round bottom flask equipped with a magnetic stirrer, a condenserand a nitrogen in/outlet adapter was charged with triflate 17b (84 mg,0.287 mmol), 4-tert-butylphenylboronic acid (77 mg, 0.43 mmol), DME (3.2ml), Na₂CO₃ (1.3 mL, 2.0M). The resulting solution was degassed for 15min, then Pd(PPh₃)₄ (33 mg, 0.03 mmol) was added. The reaction mixturewas warmed to 80° C. and stirred for 1 h. After cooled to roomtemperature, the reaction mixture was diluted with EtOAc and washed withsaturated NaHCO₃, brine, dried over Na₂SO₄. The organic layer wasconcentrated under reduced pressure and purified on silica gel. Elutionwith EtOAc/hexanes solvent system afforded the desired compound (80 mg,100% yield). ¹H NMR (300 MHz, CDCl₃) δ 9.02 (d, J=4.5 Hz, 1H), 8.89 (d,J=4.5 Hz, 1H), 7.76 (d, J=6.6 Hz, 2H), 7.65 (d, J=4.2 Hz, 1H), 7.58 (d,J=8.4 Hz, 2H), 7.50 (d, J=4.2 Hz, 1-H), 2.91 (s, 3H), 1.41 (s, 9H).

d. Preparation of Compound 17d

A mixture of substitited napthayridine 17c (80 mg, 0.29 mmol), NBS (68mg, 0.376 mmol) in carbon tetrachloride (10.0 mL) was heated under lightfor 1 h. The solids were filtered and the solvent was removed to givethe crude product. Purification using 0-50% ethyl acetate in hexaneafforded the product (50 mg, 49% yield) along with some dibrominatedproduct. ¹H NMR (300 MHz, CDCl₃) 9.07 (d, J=4.2 Hz, 1H), 9.02 (d, J=4.5Hz, 1-H), 7.77-7.70 (m, 4H), 7.59 (d, J=8.4 Hz, 2H), 5.25 (s, 2H), 1.42(s, 9H).

e. Preparation of Compound 17e

A 25-mL round bottom flask equipped with a magnetic stirrer, a condenserand a nitrogen in/outlet adapter was charged with bromomethylintermediate 17d (25 mg, 0.070 mmol), DMF (2 mL), K₂CO₃ (20 mg, 0.14mmol), and 1,3-bis(tert-butoxycarbonyl)guanidine (27 mg, 0.11 mmol) Thereaction mixture was stirred at 50° C. for 16 h. The reaction mixturewas diluted with EtOAc, washed with water, 10% LiCl, brine, dried overNa₂SO₄, concentrated, and purified on silica gel. Elution with 100%EtOAc afforded the desired compound as a white solid (27 mg, 70% yield).¹H NMR (300 MHz, CDCl₃) 9.5 (bs, 2H), 8.96-8.93 (m, 2H), 7.74 (d, J=8.1Hz, 2H), 7.65-7.63 (m, 1H), 7.55 (d, J=8.1 Hz, 2H), 7.32 (d, J=4.2 Hz,1H), 5.98 (s, 2H), 1.42 (s, 9H), 1.38 (s, 9H), 1.16 (s, 9H).

Example 18 Preparation of Compound 18

To a solution of azide 18a (9 mg, 0.028 mmol) in 0.9 mL THF and 0.1 mLH₂O was added polymer supported PPh₃ (47 mg) and the mixture was stirredfor 16 h. The solid was filtered off and the solvents were removed undervacuuo. The resulting residue was dissolved in MeOH and was purified inISCO eluting with CH₂Cl₂ to (10/89/1:MeOH/CHCl₃/ammonium hydroxide)which afforded the title compound as white solid (4 mg, 49% yield). ¹HNMR (300 MHz, CDCl₃) δ 9.06 (m, 1H), 9.0 (m, 1H), 7.8 (m, 4H), 7.64 (m,2H), 5.15 (s, 2H), 1.43 (s, 9H).

The requisite intermediates were prepared as follows:

a. Preparation of Compound 18a

To a solution of the bromide 17d (17 mg, 0.048 mmol) in 1.0 mL DMF wasadded NaN₃ (5.5 mg, 0.085 mmol) and the reaction mixture was stirred for12 h. After the completion of the reaction, the solvent was removed, theresidue was diluted with ethyl acetate and was washed with NaHCO₃ andbrine provided the product (9 mg, 60% yield) used as crude for thereduction step.

Example 19 Preparation of Compound 19

A 10-mL vial was added di-tert-butyl guanidine compound 19e (20 mg,0.037 mmol), CH₂Cl₂ (0.5 mL), and TFA (0.5 mL). The sealed vial wasstirred at rt overnight. The solvent was removed and the residue waspurified on silica gel. Elution with CH₂Cl₂ to(10/89/1:MeOH/CHCl₃/ammonium hydroxide) afforded the title compound aswhite solid (7 mg, 57% yield). ¹H NMR (300 MHz, CD₃OD) δ 8.39 (d, J=8.1Hz, 1H), 8.29-8.23 (m, 2H), 8.15 (m, 1H), 7.77-7.70 (m, 4H), 5.30 (s,2H), 1.44 (s, 9H).

The requisite intermediates were prepared as follows.

a. The Intermediate 19a

is commercially available.b. Preparation of Compound 19b

A mixture of 4-methylpthalazin-1-ol 19a (200 mg, 1.25 mmol) in 2.0 mLPOCl₃ was heated in a sealed tube at 115° C. for 2 h. The reactionmixture was cooled down and the residue was purified in ISCO using 0-50%EtOAC in hexane to afford the desired product (150 mg, 85% yield). ¹HNMR (CDCl₃, 300 MHz) δ 8.34 (m, 1H), 8.11 (m, 1H), 8.02 (m, 2H), 3.08(s, 3H).

c. Preparation of Compound 19c

A 25-mL round bottom flask equipped with a magnetic stirrer, a condenserand a nitrogen in/outlet adapter was charged with1-chloro-4-methylpthalazine 19b (150 mg, 0.843 mmol),4-tert-butylphenylboronic acid (225 mg, 1.26 mmol), DME (10 mL), Na₂CO₃(3.8 mL, 2M). The resulting solution was degassed for 15 min, thenPd(PPh₃)₄ (93 mg, 0.084 mmol) was added. The reaction mixture was warmedto 100° C. and stirred for 3 h. After cooled to room temperature, thereaction mixture was diluted with EtOAc and washed with saturatedNaHCO₃, brine, dried over Na₂SO₄. The organic layer was concentratedunder reduced pressure and purified on silica gel. Elution withEtOAc/hexanes solvent system afforded the desired compound (150 mg, 64%yield). ¹H NMR (300 MHz, CD₃OD) δ 8.34 (m, 1H), 8.09-7.97 (m, 3H),7.69-7.62 (m, 4H), 3.04 (s, 3H), 1.42 (s, 9H).

d. Preparation of Compound 19d

A mixture of substitited pthalazine 19c (150 mg, 0.543 mmol), NBS (147mg, 0.815 mmol) in carbon tetrachloride (2.0 mL) was heated under lightfor 2 h. The solids were filtered and the solvent was removed to givethe crude product. Purification using 0-50% ethyl acetate in hexaneafforded the product along with some dibrominated product and somestarting material as a mixture. This mixture was used for next stepwithout further separation.

e. Preparation of Compound 19e

A 25-mL round bottom flask equipped with a magnetic stirrer, a condenserand a nitrogen in/outlet adapter was charged with above mixture 19d (23mg, 0.059 mmol), DMF (1.0 mL), K₂CO₃ (16 mg, 0.118 mmol), and1,3-bis(tert-butoxycarbonyl)guanidine (23 mg, 0.089 mmol) The reactionmixture was stirred at 50° C. for 16 h. The reaction mixture was dilutedwith EtOAc, washed with water, 10% LiCl, brine, dried over Na₂SO₄,concentrated, and purified on silica gel. Elution with 5% EtOAc/hexanesafforded the title compound as a white solid (20 mg). ¹H NMR (300 MHz,CDCl₃) δ 9.55 (bs, 2H), 8.21-8.14 (m, 2H), 7.88 (m, 2H), 7.71 (d, J=8.4Hz, 2H), 7.58 (d, J=8.1 Hz, 2H), 5.98 (s, 2H), 1.42-1.22 (9H×3).

Example 20 Preparation of Compound 20

A 10-mL vial was added di-tert-butyl guanidine compound 20d (40 mg,0.075 mmol), CH₂Cl₂ (1.0 mL), and TFA (1.0 mL). The sealed vial wasstirred at rt overnight. The solvent was removed and the residue waspurified on silica gel. Elution with CH₂Cl₂ to(10/89/1:MeOH/CHCl₃/anunonium hydroxide) afforded the desired compoundas white solid (12 mg, 48% yield). ¹H NMR (300 MHz, CD₃OD) δ 8.73 (t,J=1.8 Hz, 1H), 8.48 (dt, J=8.1, 1.5 Hz, 1H), 8.21-8.12 (m, 2H),8.04-7.98 (m, 1H), 7.77-7.71 (m, 1H), 7.63-7.59 (m, 1H), 7.48 (t, J=7.8Hz, 1H), 5.25 (s, 2H), 1.44 (s, 9H).

The requisite intermediates were prepared as follows.

a. The Compound 20a

is commercially available.b. Preparation of Compound 20b

A 25-mL round bottom flask equipped with a magnetic stirrer, a condenserand a nitrogen in/outlet adapter was charged with2-chloro-4-methylquinazoline 20a (250 mg, 1.4 mmol),3-tert-butylphenylboronic acid (373 g, 2.1 mmol), DME (16 ml), Na₂CO₃(6.3 mL, 2.0M). The resulting solution was degassed for 15 min, thenPd(PPh₃)₄ (161 mg, 0.14 mmol) was added. The reaction mixture was warmedto 85° C. and stirred for 5 h. After cooled to room temperature, thereaction mixture was diluted with EtOAc and washed with saturatedNaHCO₃, brine, dried over Na₂SO₄. The organic layer was concentratedunder reduced pressure and purified on silica gel. Elution withEtOAc/hexanes solvent system afforded the desired compound (243 mg, 63%yield). ¹H NMR (300 MHz, CDCl₃) δ 8.66 (s, 1H), 8.42 (d, J=7.5 Hz, 1H),8.08 (d, J=9.0 Hz, 2H), 7.86 (t, J=7.2 Hz, 1H), 7.60-7.43 (m, 3H), 3.02(s, 3H), 1.43 (s, 9H).

c. Preparation of Compound 20c

A mixture of substituted 4-methylquinazoline 20b (223 mg, 0.808 mmol),NBS (380 mg, 2.1 mmol) in carbon tetrachloride (3.0 mL) was heated underlight for 16 h. The solids were filtered and the solvent was removed togive the crude product. Purification using 10% ethyl acetate in hexaneafforded the product (311 mg) as a mixture with some dibrominatedproduct and some starting material. This material was used for the nextstep without further purification.

d. Preparation of Compound 20d

A 25-mL round bottom flask equipped with a magnetic stirrer, a condenserand a nitrogen in/outlet adapter was charged with above bromide mixture20c (144 mg, 0.41 mmol), DMF (2 mL), K₂CO₃ (112 mg, 0.811 mmol), and1,3-bis(tert-butoxycarbonyl)guanidine (156 mg, 0.61 mmol) The reactionmixture was stirred at 50° C. for 2 h. The reaction mixture was dilutedwith EtOAc, washed with water, 10% LiCl, brine, dried over Na₂SO₄,concentrated, and purified on silica gel. Elution with 0-50%EtOAc/hexanes afforded the title compound as a white solid (45 mg). ¹HNMR (300 MHz, CDCl₃) δ 9.75 (bs, 2H), 8.70 (t, J=1.3 Hz, 1H), 8.41 (dt,J=5.8, 1.0 Hz, 1H), 8.09 (d, J=6.2 Hz, 1H), 8.02 (d, J=5.8 Hz, 1H),7.88-7.84 (m, 1H), 7.59-7.50 (m, 1H), 7.49 (m, 1H), 7.42 (t, J=5.8 Hz,1H), 5.94 (s, 2H), 1.39 (s, 18H), 1.23 (s, 9H).

Example 21 Preparation of Compound 21

A 10-mL vial was added di-tert-butyl guanidine compound 21d (85 mg,0.159 mmol), CH₂Cl₂ (1 mL), and TFA (1 mL). The sealed vial was stirredat rt overnight. The solvent was removed and the residue was purified onsilica gel. Elution with CH₂Cl₂ to (10/89/1:MeOH/CHCl₃/ammoniumhydroxide) afforded the desired compound (47 mg, 87% yield); ¹H NMR (300MHz, CD₃OD) δ 9.55 (s, 1H), 8.41 (t, J=1.5 Hz, 1H), 8.17-8.40 (m, 2H),7.88 (m, 2H), 7.67 (m, 1H), 7.58 (t, J=7.8 Hz, 1H), 5.15 (s, 2H), 1.47(s, 9H).

The requisite intermediates were prepared as follows:

a. Preparation of Compound 21a

Prepared by following literature method: PCT Int. Appl. 2007107965, 27Sep. 2007, Hubschwerlen, Christian, Rueedi, Georg, SurivetJean-Philippe, Zumbrunn Acklin, Cornelia

b. Preparation of Compound 21b

A 50-mL round bottom flask equipped with a magnetic stirrer, a condenserand a nitrogen in/outlet adapter was charged with2-chloro-8-methylquinoxaline 21a (340 mg, 1.8 mmol),3-tert-butylphenylboronic acid (605 mg, 3.4 mmol), water/dioxane (1 mL/3ml), K₂CO₃ (470 mg, 3.4 mmol). The resulting solution was degassed for 5min, then Pd(PPh₃)₄ (80 mg) was added. The reaction mixture was warmedto 100° C. and stirred for 3 h. After cooled to room temperature, thereaction mixture was diluted with EtOAc (100 mL) and washed withsaturated NaHCO₃ (30 mL), brine (30 mL), dried over Na₂SO₄. The organiclayer was concentrated under reduced pressure and purified on silicagel. Elution with EtOAc/hexanes solvent system afforded the titlecompound 21b (150 mg, 30% yield). LC/MS 277.13 (M+H).

c. Preparation of Compound 21c

A mixture of substituted quinoxaline 21b (130 mg, 0.47 mmol), NBS (92mg, 0.518 mmol) in carbon tetrachloride (5.0 mL) was heated under lightfor 2 h. The solids were filtered and the solvent was removed to givethe crude product. Purification using 10% ethyl acetate in hexaneafforded the product 21c (75 mg, 45% yield). ¹H NMR (300 MHz, CDCl₃) δ9.38 (s, 1H), 8.37 (s, 1H), 8.11-8.06 (m, 2H), 7.88 (d, J=6.9 Hz, 1H),7.70 (t, J=7.2 Hz, 1H), 7.59-7.5 (m, 2H), 5.27 (s, 2H), 1.44 (s, 9H).

d. Preparation of Compound 21d

A 25-mL round bottom flask equipped with a magnetic stirrer was chargedwith bromomethyl intermediate 21c (110 mg, 0.309 mmol), DMF (4 mL),K₂CO₃ (85 mg, 0.618 mmol), and 1,3-bis(tert-butoxycarbonyl)guanidine(103 mg, 0.403 mmol) The reaction mixture was stirred at 50° C. for 2hours. The reaction mixture was diluted with EtOAc, washed with water(10 mL), 10% LiCl, brine, dried over Na₂SO₄, concentrated, and purifiedon silica gel. Elution with 5% EtOAc/hexanes afforded the title compoundas a white solid 1,3-bis(t-butoxycarbonyl)-guanidine 21d (100 mg, 61%yield). ¹H NMR (300 MHz, CDCl₃) δ 9.6 (bs, 1H), 9.45 (bs, 1H), 9.36 (s,1H), 8.28 (s, 1H), 8.06-8.98 (m, 2H), 7.68 (t, J=8.1 Hz, 1H), 7.56-7.47(m, 3H), 6.04 (s, 2H), 1.42-1.12 (3×9H).

Example 22 Preparation of Compound 22

A 10-mL vial was added di-tert-butyl guanidine compound 22d (90 mg,0.168 mmol), CH₂Cl₂ (1 mL), and TFA (1 mL). The sealed vial was stirredat room temperature overnight. The solvent was removed and the residuewas purified on silica gel. Elution with CH₂Cl₂ to(10/89/1:MeOH/CHCl₃/ammonium hydroxide) afforded the desired compound(50 mg, 91% yield). LCMS: 334.05

The requisite intermediates were prepared as follows:

a. Preparation of Compound 22a

The compound was prepared as described by Fahr, Bruce T., et al.,Bioorganic & Medicinal Chemistry Letters, 2006, 16(3), 559-562.

b. Preparation of Compound 22b

A 50-mL round bottom flask equipped with a magnetic stirrer, a condenserand a nitrogen in/outlet adapter was charged with2-chloro-6-methylquinoxaline 22a (250 mg, 1.4 mmol),3-tert-butylphenylboronic acid (400 mg, 2.1 mmol), water/dioxane (1 mL/3ml), K₂CO₃ (386 mg, 2.8 mmol). The resulting solution was degassed for 5min, then Pd(PPh₃)₄ (30 mg) was added. The reaction mixture was warmedto 100° C. and stirred for 3 hours. After cooled to room temperature,the reaction mixture was diluted with EtOAc and washed with saturatedNaHCO₃, brine, dried over Na₂SO₄. The organic layer was concentratedunder reduced pressure and purified on silica gel. Elution withEtOAc/hexanes solvent system afforded the title compound 22b as oil (280mg, 72% yield). LC/MS 277.13 (M+H).

c. Preparation of Compound 22c

A mixture of substituted quinoxaline 22b (270 mg, 1.1 mmol), NBS (213mg, 1.2 mmol) in carbon tetrachloride (5.0 mL) was heated under lightfor 2 hours. The solids were filtered and the solvent was removed togive the crude product. Purification using 10% ethyl acetate in hexaneafforded the product 22c as a mixture of monobromo, dibromo and somestarting material which was used for the next step.

d. Preparation of Compound 22d

A 25-mL round bottom flask equipped with a magnetic stirrer was chargedwith 22c and its dibromo derivative (200 mg), DMF (5 mL), K₂CO₃ (200mg), and 1,3-bis(tert-butoxycarbonyl)guanidine (200 mg) The reactionmixture was stirred at 50° C. for 2 hours. The reaction mixture wasdiluted with EtOAc, washed with water (10 mL), 10% LiCl, brine, driedover Na₂SO₄, concentrated, and purified on silica gel. Elution with 5%EtOAc/hexanes afforded the desired compound 22d (110 mg).

Example 23

The following can illustrate representative pharmaceutical dosage forms,containing a compound of formula I (‘Compound X’) or a pharmaceuticallyacceptable salt thereof, for therapeutic or prophylactic use in humans.

(i) Tablet 1 mg/tablet Compound X = 100.0 Lactose 77.5 Povidone 15.0Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesiumstearate 3.0 300.0

(ii) Tablet 2 mg/tablet Compound X = 20.0 Microcrystalline cellulose410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0500.0

(iii) Capsule mg/capsule Compound X = 10.0 Colloidal silicon dioxide 1.5Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0

(iv) Injection 1 (1 mg/ml) mg/ml Compound X = (free acid form) 1.0Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodiumchloride 4.5 1.0N Sodium hydroxide solution q.s. (pH adjustment to7.0-7.5) Water for injection q.s. ad 1 mL

(v) Injection 2 (10 mg/ml) mg/ml Compound X = (free acid form) 10.0Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethyleneglycol 400 200.0 0.1N Sodium hydroxide solution q.s. (pH adjustment to7.0-7.5) Water for injection q.s. ad 1 mL

(vi) Aerosol mg/can Compound X = 20.0 Oleic acid 10.0Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,000.0Dichlorotetrafluoroethane 5,000.0The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

What is claimed is:
 1. A method for treating a bacterial infection in amammal comprising administering to the mammal an effective amount of abicyclic heteroaromatic ring compound of formulae selected from:

Wherein: R¹is phenyl that is substituted with one or more groupsindependently selected from halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl,—C(═O)NR^(e)R^(f), and phenyl that is optionally substituted with one ormore halo, or (C₁-C₆)alkyl, R² is —NR^(c)R^(d), —N⁺(R₃)Z⁻, or—NR^(a)C(=NR^(a))—NR^(c)R^(d), or R² is (C₁-C₆)alkyl that is substitutedwith —NR^(c)R^(d), —N⁺(Ra)₃ Z⁻, —NR^(a)C(═NR^(a))—NR^(c)R^(d), or—NR^(a)—C(═NR^(a))—R^(a), each R^(a) is independently H, or(C₁-C₆)alkyl, each R^(c) and R^(d) is independently selected from H, or(C₁-C₆)alkyl that is optionally substituted with one or more hydroxy oramino; or R^(c) and R^(d) togather with the nitrogen to which they areattached form a aziridino, azetidino, morpholino, piperazino,pyrrolidino or piperidino; each R^(e) and R^(f) is independentlyselected from H, or (C₁-C₆)alkyl that is optionally substituted with oneor more hydroxy or amino; or R^(e) and R^(f) togather with the nitrogento which they are attached form a aziridino, azetidino, morpholino,piperazino, pyrrolidino or piperidino; and each Z⁻ is independently asuitable counter ion; or a pharmaceutical acceptable salt thereof. 2.The method of claim 1 wherein R¹ is, 3-biphenyl, 3-tert-butylphenyl,4-tert-butylphenyl, 3-fluorophenyl,3-methoxycarbonyl-5-(4-tert-butylphenyl)phenyl, 3-aminocarbonyl-5-(4-tert-butylphenyl)phenyl,3-(N-(2-hydroxyethyl)aminocarbonyl)-5-(4-tert-butylphenyl)phenyl, or3-methylphenyl.
 3. The method of claim 1 wherein R² is guanadinomethyl,2-aminoethylamino, aminomethyl, —CH₂—NH—C(═NH)—CH₃, or—CH₂—N═C(NH₂)—NH_(2.)
 4. The method of claim 1 wherein the compound isselected from:


5. The method of claim 1 wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 6. A method for treatinga bacterial infection in a mammal comprising administering to the mammalan effective amount of compound of formulae selected from:


7. The method of claim 1 or claim 5 wherein the bacterial infection is aGram-negative bacterial strain infection.
 8. The method of claim 7wherein the Gram-negative bacterial strain is selected from the groupconsisting of Escherchia coli, Caulobacter crescentus, Pseudomonasaeruginosa, Agrobacterium tumefaciens, Branhamella catarrhalis,Citrobacter diversus, Enterobacter aerogenes, Enterobacter cloacae,Enterobacter sakazakii, Enterobacter asburiae, Pantoea agglomerans,Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella rhinoscleromatis,Proteus mirabilis, Salmonella typhimurium, Salmonella enteriditis,Serratia marcescens, Shigella sonnei, Neisseria gonorrhoeae,Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacterlwoffi, Salmonella enteriditis, Fusobacterium nucleatum, Veillonellaparvula, Bacteroides forsythus, Actinobacillus actinomycetemcomitans,Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis,Helicobacter pylori, Francisella tularensis, Yersinia pestis, Borreliaburgdorferi, Neisseria meningitidis and Haemophilus influenzae.
 9. Themethod of claim 1 or claim 5 wherein the bacterial infection is aGram-positive bacterial strain infection.
 10. The method of claim 9wherein the Gram-positive bacterial strain is selected from the groupconsisting of Staphylococcus aureus, Staphylococcus epidermidis,Staphylococcus saprophyticus, Streptococcus pyogenes, Streptococcusfaecalis, Enterococcus faecalis, Enterococcus faecium, Bacillussubtilis, Micrococcus luteus, Mycobacterium tuberculosis, Bacillusanthracis, Bacillus cereus, Clostridium difficile, Propionibacteriumacnes, Streptococcus mutans, Actinomyces viscosus, Actinomycesnaeslundii, Streptococcus sanguis, Streptococcus pneumoniae andStreptococcus salivarius.
 11. The method of claim 1 or claim 5 whereinthe bacterial infection is a multiple drug-resistant bacterial straininfection.
 12. The method of claim 11 wherein the multipledrug-resistance bacterial strain is selected from the group consistingof methicillin-resistant Staphylococcus aureus, vancomycin-resistantEnterococcus, multiple drug-resistant tuberculosis andmultidrug-resistant Clostridium difficile.